The objective of this proposal is to chronically expose (1-6 months) animals to representative carbamate and organophosphate insecticides and determine the physiological, biochemical and pathological actions at the neuromuscular junction. Animals will be exposed to the agents both directly (through subcutaneous injection) and indirectly (through drinking water) and will be studied after weekly exposure for the initial 2 months followed by monthly analysis for the remaining 4 months. Specifically, the effects of chronic insecticide exposure will be studied on: (1) acetylcholine release: (2) nicotinic receptor number and sensitivity; (3) acetylcholinesterase and cholinesterase activities in nerve, muscle and blood; and (4) the development of skeletal muscle fiber necrosis. Evidence of adaptation of the neuromuscular junction to chronic insecticide exposure will be assessed by behavioral observations of muscle weakness and fasciculation and quantitated by physiological, biochemical and pathological measurements. If evidence of adaptation is present, the significance of this phenomenon and the specific neuromuscular functions affected will be elucidated. In addition to measurements of neuromuscular parameters, the activity of the microsomal mixed-function oxidase system will also be measured, to determine if the insecticides cause enzyme induction leading to alterations in their metabolism with a subsequent effect on potency.